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Agents targeting vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR) are part of systemic therapy in advanced colorectal cancer. It is well known that only certain molecular subpopulations profit from EGFR antibodies, restricting those therapeutics to a smaller fraction of patients. Recently investigated, the monitoring of temporally changing RAS mutational status by liquid biopsy might allow the application of EGFR antibodies to an additional subset of patients. In addition, KRAS G12C inhibitors combined with anti-EGFR antibodies are currently under investigation in clinical trials and could provide another effective therapy in case of KRAS G12C mutations. Beyond RAS, therapy guided by microsatellite instability (MSI) status, BRAF mutations, HER2 overexpression and NTRK fusions are welcome additions to targeted treatment in advanced colorectal cancer.